1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), available as a synthetic chemical intermediate for over 30 years, has recently been recognized to be selectively neurotoxic to cells in the zona compacta of the substantia nigra in humans and nonhuman primates. The resulting clinical syndrome in humans is virtually indistinguishable from idiopathic Parkinson's disease (IPD). The first objective of this project is to study the histological and biochemical nature of a newly created MPTP-induced squirrel monkey model for IPD. Our second goal is to study chronic low dose exposure to MPTP, in the squirrel monkey, in an attempt to more accurately reproduce the neuropathologic features of IPD, including the Lewy bodies. Thirdly, we intend to elucidate mechanism of action of MPTP. To accomplish this, acute high doses of MPTP are given to monkeys which are then sacrificed at specific time intervals, ranging from 1/2 hour to 2 weeks. Tissue is analyzed to determine metabolites of MPTP and the evolution of CNS neurotransmitter changes. In addition, it is hoped that a metabolite may be discovered which is effective in extending this animal model of IPD to rodents, our fourth goal. Autoradiographic studies will be employed to define the anatomical distribution and potential sites of action of MPTP in the squirrel monkey brain. Finally, a variety of neuropharmacologic agents, including opiates, will be given prior to MPTP exposure, in an effort to study potential receptor site of MPTP action. Our long-term goal is to use the animal model of Parkinson's disease as a vehicle for advancing our knowledge and understanding of this incurable and common neurodegenerative disease of aging.